An Uncertain Future for Durvalumab in Lung Cancer Management
Durvalumab's optimal clinical role in managing lung cancer remains unclear and more robust predictive biomarkers are needed.
The U.S. Food and Drug Administration (FDA) recently granted durvalumab Breakthrough Therapy Designation for treating locally-advanced non-small cell lung cancer (NSCLC). But this immune checkpoint inhibitor's optimal clinical role in managing lung cancer remains unclear and more robust predictive biomarkers are needed.
A growing number of immune checkpoint inhibitors are now therapeutic options for patients with advanced non-small cell lung cancer (NSCLC), with more of these immunotherapies in clinical development.1-4
Durvalumab is a high-affinity, highly-specific PD-L1-targeting human monoclonal antibody.5 The U.S. Food and Drug Administration (FDA) granted durvalumab a Breakthrough Therapy Designation in July 2017 for treating patients with unresectable, locally advanced NSCLC, based on an interim analysis of progression-free survival (PFS) data from the phase 3 PACIFIC (ClinicalTrials.gov Identifier: NCT02125461). The designation means that the FDA believes preliminary data suggest that durvalumab might prove to demonstrate “substantial improvement” over existing treatment options and allows the agency to hasten the regulatory review process.
Early phase clinical studies showed promising activity, with an overall response rate (ORR) ranging from 14% to 27% overall in early-phase efficacy and safety trials (and 23% to 29% in patients with PD-L1 overexpression, compared with 5% to 11% for those with low or no PD-L1 expression), with acceptable toxicity for durvalumab monotherapy.1,3,5
However, in the investigational combination treatment of durvalumab plus tremelimumab, treatment-related serious adverse events were reported in 36% of patients with NSCLC, including 3 treatment-related deaths.6 The maximum tolerated dose for durvalumab has been found to be 20 mg/kg every 4 weeks in combination with tremelimumab (1 mg/kg).6 As with pembrolizumab and other immune checkpoint inhibitors, myasthenia gravis has been reported following durvalumab plus tremelimumab.6,7 Another patient with advanced NSCLC who was treated with the combination developed inflammatory myopathy.8
The ongoing phase 3 PACIFIC study enrolled 713 patients whose NSCLC had responded to platinum-based chemoradiotherapy; they were administered placebo or durvalumab. Durvalumab is also under clinical investigation as a monotherapy or combination therapy (with tremelimumab, a monoclonal antibody that targets cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) for NSCLC in the phase 3 MYSTIC (ClinicalTrials.gov Identifier: NCT02453282), NEPTUNE (ClinicalTrials.gov Identifier: NCT02542293), ARCTIC (ClinicalTrials.gov Identifier: NCT02352948) and ADJUVANT (ClinicalTrials.gov Identifier: NCT02273375) trials.
While overall survival data are still awaited from the MYSTIC study of patients with stage IV metastatic NSCLC, PFS outcomes were disappointing; first-line durvalumab alone or in combination with tremelimumab failed to prolong patients' PFS compared to platinum-based chemotherapy, the current standard of care.6
While no head-to-head comparison trial data are available, the evidence base does not suggest that durvalumab monotherapy represents an improvement over nivolumab, pembrolizumab, or atezolizumab in efficacy or toxicity among patients diagnosed with NSCLC.5 Comparisons of these trials' outcomes have been discouraged because patient selection was conducted using different PD-L1 assays, potentially yielding important differences in disease biology between the studies' patient populations.5
“Durvalumab has been extensively studied,” said Tawee Tanvetyanon, MD, MPH, a medical oncologist at the Moffitt Cancer Center in Tampa, Florida. “The MYSTIC study is disappointing and durvalumab will unlikely be able to become a first-line choice, especially now that pembrolizumab has dominated in this setting.”
Concurrent carboplatin/paclitaxel is a “very popular regimen” in the United States, Dr Tanvetyanon noted. “So I think it is not known how well durvalumab will fit in the current practice.”